Stress that takes place early in life promotes cognitive deficits and accelerated loss of learning and memory during middle age. This is of major clinical importance because childhood neglect and maltreatment is a severe yet underappreciated global public health problem, associated with neurological and cognitive dysfunction. However, the processes and mechanisms by which chronic early-life stress (ES) result in long- lasting decline of hippocampus- mediated learning and memory are unclear. In a rat model of ES generated in our lab, chronic stress during postnatal days 2-9 results in learning and memory deficits during middle age (10-12 months of age). These cognitive deficits are accompanied by loss of plasticity in hippocampal CA3- CA1 synapses, atrophied apical dendritic trees, and chronically increased levels of the stress-activated neuropeptide corticotropin-releasing hormone (CRH). Two fundamental gaps in our understanding of these dramatic effects of ES on cognition and plasticity in hippocampus remain, and are addressed in my proposal: 1) Are the long-term effects of ES on hippocampal structure and function a result of changes in hippocampal maturation that take place during a critical period (i.e. the first 3 weeks of life) or changes that become progressively prominent over time? To answer this question, we will examine whether these changes can be reversed only during the time of postnatal hippocampal development (postnatal (P) days 10-17), or also during early adulthood (2-3 months of age), when hippocampal connectivity is fully established. 2) Which molecules mediate the effects of ES on the hippocampus, and specifically, what is the role of the endogenous hippocampal stress hormone CRH in the process by which ES deranges the hippocampus? Supported by preliminary data, we will directly examine this hypothesis by infusing a selective blocker of the CRH type 1 receptor into the lateral ventricles of ES rats, either immediately after the ES period (PI 0-17) or in young adult, ES graduates (at age P72-78). Hippocampal structure and function will be assessed by measuring long-term potentiation (LTP), testing learning and memory in behavioral tasks, and observing dendritic structure of hippocampal neurons at 10-12 months of age, when the consequences of ES are apparent. This project supports the idea that late-onset cognitive disorders may actually be born in early stages of development, before symptoms of disability appear. Elucidating the contributions of early adverse experiences to the mechanisms of neurological disorders will allow for potential therapeutic interventions to offset the consequences of ES.